Summary ? Neuroblastoma is the most common extracranial tumor in childhood, with poor clinical outcomes for high-risk patients using systemic, multi-drug chemotherapy followed by surgical resection. There is a strong clinical need for new approaches to chemotherapy administration due to poor outcomes and secondary organ toxicities with long-term negative consequences particularly in children. The goal of this proposal is to develop focal drug delivery systems that can be applied within the tumor or over a post-resection tumor bed. The hypothesis is that local delivery coupled with sustained drug release using silk protein-based biomaterial sponges and films (implantable) or gels (injectable) will provide new therapeutic strategies for high-risk neuroblastoma patients while reducing systemic side effects. We will build upon our extensive prior experience and success using silk biomaterials for sustained drug release to optimize local tumor treatment while minimizing the impact on healthy tissue. This will include targeting tumor drug concentration to match or exceed clinical blood levels on a sustained basis, as well as exploiting directional diffusion to further improve targeting to the tumor site versus healthy tissue. The focus will be on delivering cytotoxic chemotherapeutic agents (doxorubicin, vincristine, etoposide-4'-phosphate, cisplatin) in both single and dual drug-loaded delivery systems using silk biomaterials. These silk delivery systems will be assessed in vitro for impact on neuroblastoma cell lines and in vivo using an orthotopic tumor models generated from neuroblastoma cell lines and patient-derived xenografts. Drug release kinetics and toxicity will be assessed in the animal models to assess the impact of local drug release on tumor growth as well as pharmacokinetics and toxicity in tissue compartments. All studies are supported by extensive preliminary data and represent a collaborative team consisting of a bioengineer (Kaplan) with expertise with the biomaterials and drug delivery and a physician (Chiu) who focuses on neuroblastoma treatments.